Periodontitis is an inflammatory disease with host-parasite interactions known to contribute to connective tissue destruction and alveolar bone resorption the landmark of this disease. Porphyromonas gingivalis (P.g.), a black-pigmented Gram-negative anaerobic bacterium, has been implicated as a major periodontal pathogen in the development and progression of periodontal disease. Structures on its bacterial cell wall and appendage, such as lipopolysaccharide (LPS) and fimbriae, play important roles in the induction of innate immune responses, including cytokine production by localized and circulating leukocytes, such as monocyte/macrophage. Based on our preliminary data, we hypothesize that live P.g. stimulates unique pro-inflammatory signal transduction pathways in human PBM as opposed to purified bacterial components, such as P.g. LPS or P.g. fimbriac. To test this, the following specific aims are proposed: Aim 1: To test at the transcriptional level the hypothesis that unique signaling pathways are differentially induced by live P.g., P.g. LPS and P.g. fimbriae in human peripheral blood monocytes. Aim 2: To test at the level of protein expression the hypothesis that unique signaling pathways are differentially induced by live P.g., P.g. LPS and P.g. fimbriac in human PBM. Aim 3: To establish the functional significance of unique signaling pathways identified in Aims 1 and 2 we will test them in vitro and in vivo. The results of these studies should provide a new gateway to our understanding of the etiology and pathogenesis of periodontal diseases. Since the differential host innate response identified in our preliminary data may in fact represent different stages of the periodontal infection, the results are expected to have important therapeutic implications.